Molecular Cardiology

Pavia, Italy

Molecular Cardiology

Pavia, Italy
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News Article | February 17, 2017
Site: www.marketwired.com

HUDSON, NY--(Marketwired - Feb 17, 2017) - Taconic Biosciences, a global leader in genetically engineered rodent models and associated services, announced it has generated a novel mouse model of Vici syndrome for use by two investigators studying this rare disease. As a corporate sponsor of the Rare Disease Science Challenge: BeHEARD, hosted by the Rare Genomics Institute, Taconic donated model development services. Using CRISPR/Cas9 gene editing, Taconic developed and validated a mouse model carrying the EPG5 mutation found in Vici syndrome patients in multiple families. A highly efficient way to generate custom mouse and rat models on a short timeline, CRISPR is one of many technologies Taconic employs to generate models of human disease and support investigator studies of gene function in vivo. Genetically engineered mice of the Vici syndrome model have been delivered to the investigators working on the BeHEARD project: Mathias Gautel, BHF Chair of Molecular Cardiology at King's College London BHF Research Excellence Centre, and Heinz Jungbluth, Reader in Paediatric Neurology at King's College, and Consultant at the Evelina Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London. "The precision of the genetic manipulation by Taconic and their speed of delivery were critical to our work," Prof. Gautel and Dr. Jungbluth said. The investigators are now using the mice to validate the model's replication of the human phenotype of the disease, in terms of neurological, musculoskeletal and other organ symptoms. "If the model replicates the human phenotype with significant fidelity, it could be applied quite rapidly to screening drug compounds for Vici syndrome," Prof. Gautel said. Rachel and Michael Harris, parents of 10-year-old Vici syndrome patient David, submitted the proposal for the BeHEARD project and are hopeful the model will facilitate development of effective therapies. "While the initial research is focused upon understanding the disease mechanisms, we hope to soon see translational research that will bring new therapies to David and other patients," Michael Harris said. "Taconic's core mission is to provide animal models that help accelerate drug discovery. Being able to support critical research on a rare disease like Vici syndrome through custom genetically engineered models is extremely rewarding," said Dr. Robert Rosenthal, chief executive officer of Taconic Biosciences. Taconic has over twenty years' experience designing custom transgenic models for leading pharmaceutical, biotech and academic clients. Taconic is fully licensed to utilize CRISPR/CAS9, homologous recombination and other technologies to develop custom mouse and rat models, including humanized, knockout, knock-in, inducible shRNA, or microRNA expressing models. Vici syndrome is a severe congenital multisystem disorder characterized by a failure to develop the corpus callosum region of the brain, along with a cardiomyopathy, cataracts, hypopigmentation of the skin, eyes and hair, and a combined immunodeficiency. To learn more about Taconic's custom model generation, please call 1-888-TACONIC (888-822-6642) in the US or +45 70 23 04 05 in Europe, or email info@taconic.com. To learn more about the BeHeard Project, visit http://www.raregenomics.org/beheard-competition/. About Taconic Biosciences, Inc. Taconic Biosciences is a fully-licensed, global leader in genetically engineered rodent models and services. Founded in 1952, Taconic helps biotechnology companies and institutions acquire, custom generate, breed, precondition, test, and distribute valuable research models worldwide. Specialists in genetically engineered mouse and rat models, precision research mouse models, and integrated model design and breeding services, Taconic operates three service laboratories and six breeding facilities in the U.S. and Europe, maintains distributor relationships in Asia and has global shipping capabilities to provide animal models almost anywhere in the world.


Denegri M.,Molecular Cardiology | Avelino-Cruz J.E.,Molecular Cardiology | Boncompagni S.,University of Chieti Pescara | De Simone S.A.,Molecular Cardiology | And 10 more authors.
Circulation Research | Year: 2012

RATIONALE:: Catecholaminergic polymorphic ventricular tachycardia is an inherited disease that predisposes to cardiac arrest and sudden death. The disease is associated with mutations in the genes encoding for the cardiac ryanodine receptor (RyR2) and cardiac calsequestrin (CASQ2). CASQ2 mutations lead to a major loss of CASQ2 monomers, possibly because of enhanced degradation of the mutant protein. The decrease of CASQ2 is associated with a reduction in the levels of Triadin (TrD) and Junctin (JnC), two proteins that form, with CASQ2 and RyR2, a macromolecular complex devoted to control of calcium release from the sarcoplasmic reticulum. OBJECTIVE:: We intended to evaluate whether viral gene transfer of wild-type CASQ2 may rescue the broad spectrum of abnormalities caused by mutant CASQ2. METHODS AND RESULTS:: We used an adeno-associated serotype 9 viral vector to express a green fluorescent protein-tagged CASQ2 construct. Twenty weeks after intraperitoneal injection of the vector in neonate CASQ2 KO mice, we observed normalization of the levels of calsequestrin, triadin, and junctin, rescue of electrophysiological and ultrastructural abnormalities caused by CASQ2 ablation, and lack of life-threatening arrhythmias. CONCLUSIONS:: We have proven the concept that induction of CASQ2 expression in knockout mice reverts the molecular, structural, and electric abnormalities and prevents life-threatening arrhythmias in CASQ2-defective catecholaminergic polymorphic ventricular tachycardia mice. These data support the view that development of CASQ2 viral gene transfer could have clinical application. © 2012 American Heart Association, Inc.


Tarone G.,University of Turin | Balligand J.-L.,Catholic University of Leuven | Bauersachs J.,Medizinische Hochschule Hanover | Clerk A.,University of Reading | And 12 more authors.
European Journal of Heart Failure | Year: 2014

The failing heart is characterized by complex tissue remodelling involving increased cardiomyocyte death, and impairment of sarcomere function, metabolic activity, endothelial and vascular function, together with increased inflammation and interstitial fibrosis. For years, therapeutic approaches for heart failure (HF) relied on vasodilators and diuretics which relieve cardiac workload and HF symptoms. The introduction in the clinic of drugs interfering with beta-adrenergic and angiotensin signalling have ameliorated survival by interfering with the intimate mechanism of cardiac compensation. Current therapy, though, still has a limited capacity to restore muscle function fully, and the development of novel therapeutic targets is still an important medical need. Recent progress in understanding the molecular basis of myocardial dysfunction in HF is paving the way for development of new treatments capable of restoring muscle function and targeting specific pathological subsets of LV dysfunction. These include potentiating cardiomyocyte contractility, increasing cardiomyocyte survival and adaptive hypertrophy, increasing oxygen and nutrition supply by sustaining vessel formation, and reducing ventricular stiffness by favourable extracellular matrix remodelling. Here, we consider drugs such as omecamtiv mecarbil, nitroxyl donors, cyclosporin A, SERCA2a (sarcoplasmic/ endoplasmic Ca2 + ATPase 2a), neuregulin, and bromocriptine, all of which are currently in clinical trials as potential HF therapies, and discuss novel molecular targets with potential therapeutic impact that are in the pre-clinical phases of investigation. Finally, we consider conceptual changes in basic science approaches to improve their translation into successful clinical applications. © 2014 The Authors.


Belge C.,Catholic University of Leuven | Hammond J.,Catholic University of Leuven | Dubois-Deruy E.,Catholic University of Leuven | Manoury B.,Catholic University of Leuven | And 18 more authors.
Circulation | Year: 2014

BACKGROUND - : β1-2-adrenergic receptors (AR) are key regulators of cardiac contractility and remodeling in response to catecholamines. β3-AR expression is enhanced in diseased human myocardium, but its impact on remodeling is unknown. METHODS AND RESULTS - : Mice with cardiac myocyte-specific expression of human β3-AR (β3-TG) and wild-type (WT) littermates were used to compare myocardial remodeling in response to isoproterenol (Iso) or Angiotensin II (Ang II). β3-TG and WT had similar morphometric and hemodynamic parameters at baseline. β3-AR colocalized with caveolin-3, endothelial nitric oxide synthase (NOS) and neuronal NOS in adult transgenic myocytes, which constitutively produced more cyclic GMP, detected with a new transgenic FRET sensor. Iso and Ang II produced hypertrophy and fibrosis in WT mice, but not in β3-TG mice, which also had less re-expression of fetal genes and transforming growth factor β1. Protection from Iso-induced hypertrophy was reversed by nonspecific NOS inhibition at low dose Iso, and by preferential neuronal NOS inhibition at high-dose Iso. Adenoviral overexpression of β3-AR in isolated cardiac myocytes also increased NO production and attenuated hypertrophy to Iso and phenylephrine. Hypertrophy was restored on NOS or protein kinase G inhibition. Mechanistically, β3-AR overexpression inhibited phenylephrine-induced nuclear factor of activated T-cell activation. CONCLUSIONS - : Cardiac-specific overexpression of β3-AR does not affect cardiac morphology at baseline but inhibits the hypertrophic response to neurohormonal stimulation in vivo and in vitro, through a NOS-mediated mechanism. Activation of the cardiac β3-AR pathway may provide future therapeutic avenues for the modulation of hypertrophic remodeling. © 2013 American Heart Association, Inc.


Knoll R.,Center for Research Excellence | Iaccarino G.,University of Salerno | Tarone G.,University of Turin | Hilfiker-Kleiner D.,Molecular Cardiology | And 4 more authors.
European Journal of Heart Failure | Year: 2011

Many primary or secondary diseases of the myocardium are accompanied with complex remodelling of the cardiac tissue that results in increased heart mass, often identified as cardiac 'hypertrophy'. Although there have been numerous attempts at defining such 'hypertrophy', the present paper delineates the reasons as to why current definitions of cardiac hypertrophy remain unsatisfying. Based on a brief review of the underlying pathophysiology and tissue and cellular events driving myocardial remodelling with or without changes in heart dimensions, as well as current techniques to detect such changes, we propose to restrict the use of the currently popular term 'hypertrophy' to cardiac myocytes that may or may not accompany the more complex tissue rearrangements leading to changes in shape or size of the ventricles, more broadly referred to as 'remodelling'. We also discuss the great potential of genetically modified (mouse) models as tools to define the molecular pathways leading to the different forms of left ventricle remodelling. Finally, we present an algorithm for the stepwise assessment of myocardial phenotypes applicable to animal models using well-established imaging techniques and propose a list of parameters most suited for a critical evaluation of such pathophysiological phenomena in mouse models. We believe that this effort is the first step towards a much auspicated unification of the terminology between the experimental and the clinical cardiologists. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2011. For permissions please email: journals.permissionsoup.com.2011 © Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2011. For permissions please email: journals.permissionsoup.com.


Liu N.,New York University | Napolitano C.,New York University | Venetucci L.A.,Molecular Cardiology | Venetucci L.A.,University of Manchester | And 2 more authors.
Trends in Cardiovascular Medicine | Year: 2012

Recent studies have shown that flecainide may be an effective therapy to prevent life-threatening arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. Several hypotheses have been advanced to explain the antiarrhythmic mechanism of flecainide, including Na+ channel blockade and a direct inhibitory action on the ryanodine receptor. In this article, we review the current literature on the topic and summarize the elements of the existing debate. © 2012 Elsevier Inc.


Huang H.,Laval University | Priori S.G.,University of Pavia | Napolitano C.,Molecular Cardiology | O'Leary M.E.,Philadelphia University | Chahine M.,Laval University
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2011

Long QT syndrome type 3 (LQT3) has been traced to mutations of the cardiac Na+ channel (Nav1.5) that produce persistent Na + currents leading to delayed ventricular repolarization and torsades de pointes. We performed mutational analyses of patients suffering from LQTS and characterized the biophysical properties of the mutations that we uncovered. One LQT3 patient carried a mutation in the SCN5A gene in which the cysteine was substituted for a highly conserved tyrosine (Y1767C) located near the cytoplasmic entrance of the Nav1.5 channel pore. The wild-type and mutant channels were transiently expressed in tsA201 cells, and Na+ currents were recorded using the patch-clamp technique. The Y1767C channel produced a persistent Na+ current, more rapid inactivation, faster recovery from inactivation, and an increased window current. The persistent Na+ current of the Y1767C channel was blocked by ranolazine but not by many class I antiarrhythmic drugs. The incomplete inactivation, along with the persistent activation of Na+ channels caused by an overlap of voltage-dependent activation and inactivation, known as window currents, appeared to contribute to the LQTS phenotype in this patient. The blocking effect of ranolazine on the persistent Na+ current suggested that ranolazine may be an effective therapeutic treatment for patients with this mutation. Our data also revealed the unique role for the Y1767 residue in inactivating and forming the intracellular pore of the Nav1.5 channel. Copyright © 2011 the American Physiological Society.


Liu N.,New York University | Ruan Y.,New York University | Denegri M.,Molecular Cardiology | Bachetti T.,Molecular Cardiology | And 6 more authors.
Journal of Molecular and Cellular Cardiology | Year: 2011

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by life-threatening arrhythmias elicited by adrenergic activation. CPVT is caused by mutations in the cardiac ryanodine receptor gene (RyR2). In vitro studies demonstrated that RyR2 mutations respond to sympathetic activation with an abnormal diastolic Ca2+ leak from the sarcoplasmic reticulum; however the pathways that mediate the response to adrenergic stimulation have not been defined. In our RyR2R4496C+/- knock-in mouse model of CPVT we tested the hypothesis that inhibition of Ca2+/calmodulin-dependent protein kinase II (CaMKII) counteracts the effects of adrenergic stimulation resulting in an antiarrhythmic activity. CaMKII inhibition with KN-93 completely prevented catecholamine-induced sustained ventricular tachyarrhythmia in RyR2R4496C+/- mice, while the inactive congener KN-92 had no effect. In ventricular myocytes isolated from the hearts of RyR2R4496C+/- mice, CaMKII inhibition with an autocamtide-2 related inhibitory peptide or with KN-93 blunted triggered activity and transient inward currents induced by isoproterenol. Isoproterenol also enhanced the activity of the sarcoplasmic reticulum Ca2+-ATPase (SERCA), increased spontaneous Ca2+ release and spark frequency. CaMKII inhibition blunted each of these parameters without having an effect on the SR Ca2+ content. Our data therefore indicate that CaMKII inhibition is an effective intervention to prevent arrhythmogenesis (both in vivo and in vitro) in the RyR2R4496C+/- knock-in mouse model of CPVT. Mechanistically, CAMKII inhibition acts on several elements of the EC coupling cascade, including an attenuation of SR Ca2+ leak and blunting catecholamine-mediated SERCA activation. CaMKII inhibition may therefore represent a novel therapeutic target for patients with CPVT. © 2010 Elsevier Ltd.


Venetucci L.,Molecular Cardiology | Denegri M.,Molecular Cardiology | Napolitano C.,Molecular Cardiology | Priori S.G.,Molecular Cardiology
Nature Reviews Cardiology | Year: 2012

Regulation of calcium flux in the heart is a key process that affects cardiac excitability and contractility. Degenerative diseases, such as coronary artery disease, have long been recognized to alter the physiology of intracellular calcium regulation, leading to contractile dysfunction or arrhythmias. Since the discovery of the first gene mutation associated with catecholaminergic polymorphic ventricular tachycardia (CPVT) in 2001, a new area of interest in this field has emerged-the genetic abnormalities of key components of the calcium regulatory system. Such anomalies cause a variety of genetic diseases characterized by the development of life-threatening arrhythmias in young individuals. In this Review, we provide an overview of the structural organization and the function of calcium-handling proteins and describe the mechanisms by which mutations determine the clinical phenotype. Firstly, we discuss mutations in the genes encoding the ryanodine receptor 2 (RYR2) and calsequestrin 2 (CASQ2). These proteins are pivotal to the regulation of calcium release from the sarcoplasmic reticulum, and mutations can cause CPVT. Secondly, we review defects in genes encoding proteins that form the voltage-dependent L-type calcium channel, which regulates calcium entry into myocytes. Mutations in these genes cause various phenotypes, including Timothy syndrome, Brugada syndrome, and early repolarization syndrome. The identification of mutations associated with 'calcium-handling diseases' has led to an improved understanding of the role of calcium in cardiac physiology. © 2012 Macmillan Publishers Limited. All rights reserved.


Ruan Y.,Cardiovascular Genetic Program | Denegri M.,Molecular Cardiology | Liu N.,Cardiovascular Genetic Program | Bachetti T.,Molecular Cardiology | And 6 more authors.
Circulation Research | Year: 2010

Rationale: Sodium channel blockers are used as gene-specific treatments in long-QT syndrome type 3, which is caused by mutations in the sodium channel gene (SCN5A). Response to treatment is influenced by biophysical properties of mutations. Objective: We sought to investigate the unexpected deleterious effect of mexiletine in a mutation combining gain-offunction and trafficking abnormalities. Methods and Results: A long-QT syndrome type 3 child experienced paradoxical QT prolongation and worsening of arrhythmias after mexiletine treatment. The SCN5A mutation F1473S expressed in HEK293 cells presented a right-ward shift of steady-state inactivation, enlarged window current, and huge sustained sodium current. Unexpectedly, it also reduced the peak sodium current by 80%. Immunostaining showed that mutant Nav1.5 is retained in the cytoplasm. Incubation with 10 μmol/L mexiletine rescued the trafficking defect of F1473S, causing a significant increase in peak current, whereas sustained current was unchanged. Using a Markovian model of the Na channel and a model of human ventricular action potential, we showed that simulated exposure of F1473S to mexiletine paradoxically increased action potential duration, mimicking QT prolongation seen in the index patient on mexiletine treatment. Conclusions: Sodium channel blockers are largely used to shorten QT intervals in carriers of SCN5A mutations. We provided evidence that these agents may facilitate trafficking of mutant proteins, thus exacerbating QT prolongation. These data suggest that caution should be used when recommending this class of drugs to carriers of mutations with undefined electrophysiological properties. © 2010 American Heart Association, Inc.

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